Non-ionic contrast media, e.g. iopamidol and iohexol, for use in angiography, have enjoyed wide-spread acceptance in the diagnostic field in recent years. The primary reasons for this revolve around the fact that the frequency of adverse reactions to intravenous injection of non-ionic contrast media, compared with most ionic contrast media (e.g., diatrizoate, sodium meglumine and the like) is reduced by a factor of two.
In a limited number of cases, however, clotting has been observed during administration of the angiographic procedure utilizing non-ionic agents. Investigations into this infrequent, but disturbing, phenomenon have unanimously confirmed that the contrast media themselves, whether ionic or non-ionic, are not actively thrombogenic. Several in vitro studies agree that the ionic contrast media typically have greater anticoagulant effects as compared to their non-ionic counterparts. Careful selection of any appropriate contrast medium for angiographic procedures therefore involves a consideration of, among other factors, the inherent lower chemotoxicity of the non-ionics balanced against the greater anticoagulant effects of the ionics.
Researchers now believe this rare clotting phenomenon to be the result of the procedure employed by the practitioner. Apparently, in cases where aspirated blood is allowed to stand in the contrast material syringe, i.e. in contact with the non-ionic agent, for several minutes prior to the procedure, thrombus formation is possible. Various modifications and improvements to technique are considered to be the primary solution to this limited problem. Nevertheless, another measure to safeguard against this potential technique-induced clotting has been the utilization of anticoagulant agents. This measure is also called for in subjects who are otherwise prone to thrombus formation.
One widely used agent known for its anticoagulant activity is heparin. It is generally believed that the angiographic procedure does not warrant systemic heparin administration, although systemic heparin administration has been used, especially in subjects with histories of hyper-aggregation. Combinations of heparin and the contrast media have been tried in these types of procedures. This has not been without difficulties, however. Considering the naturally competing processes of coagulation and fibrinolysis and the problems which an imbalance in either direction may cause, that is, thromboses or hemorrhage, respectively, it is generally understood that employment of heparin is not without risks. Further, it is believed that some cases of cardiac ischaemia and ischaemic brain injury may be the result of heparinisation during angiography.
European Patent Application 0 390 242 teaches that the red blood cell aggregation in human blood can be reduced by the addition of sodium chloride to nonionic contrast medium at a concentration of 20-60 mM. This approach, however, has the undesirable effect of increasing the osmolality of the non-ionic contrast medium.
Improved compositions and methods for using non-ionic contrast media in either angiographic procedures or patients where enhanced potential for thrombus formation exists would be a useful addition to the art.